Geoffrey K. Herkes

De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.

Results of a Multicentre, Randomised Controlled Trial of Intra-Arterial Urokinase in the Treatment of Acute Posterior Circulation Ischaemic Stroke

Background: Patients with ischaemic stroke due to occlusion of the basilar or vertebral arteries may develop a rapid deterioration in neurological status leading to coma and often to death. While intra-arterial thrombolysis may be used in this context, no randomised controlled data exist to support its safety or efficacy. Methods: Randomised controlled trial of intra-arterial urokinase within 24 h of symptom onset in patients with stroke and angiographic evidence of posterior circulation vascular occlusion. Results: Sixteen patients were randomised, and there was some imbalance between groups, with more severe strokes occurring in the treatment arm. A good outcome was observed in 4 of 8 patients who received intra-arterial urokinase compared with 1 of 8 patients in the control group. Conclusions: These results support the need for a large-scale study to establish the efficacy of intra-arterial thrombolysis for acute basilar artery occlusion.

Patient Recognition of and Response to Symptoms of TIA or Stroke

Background and Purpose: Campaigns within Australia and internationally have sought to increase awareness of the emergent nature of stroke. For these initiatives to be effective it is important to gather information about delay in seeking treatment and the reasons given for the delay by people with stroke. The purpose of this study was to examine delay in seeking treatment in people with an evolving stroke or TIA and identify clinical, behavioral and demographic factors that contributed to the delay. Subjects and Methods: During a 1-year period 150 participants were given the Response to Stroke Symptoms Questionnaire. The six domains included in the questionnaire were: (1) context in which the stroke occurred; (2) antecedents to symptoms; (3) affective response to symptoms; (4) behavioral response to symptoms; (5) cognitive response to symptoms; (6) the response of others to patient symptoms. Results: The median delay time from symptom onset to admission to hospital was 4.5 h. While 41% of participants delayed less than 3 h, more than 45% delayed greater than 6 h. Independent predictors of delay time included mode of arrival at hospital with those taking an ambulance having a median delay time of 2.7 h vs. 15.4 h for those arriving by private car (p = 0.04). Gender also predicted delay with women delaying longer (p = 0.001). The first response of others was also an independent predictor of delay time (p = 0.003) with those who called the emergency services number or took the patient to hospital resulting in the shortest patient delays. Finally, if the patient appraised their symptoms as serious they had a shorter delay time (p = 0.02). Conclusions: The message about the emergent nature of stroke may be helping to improve delay times. However, there are still many people who delay greater than 3 h after symptom onset. It is important to direct education programs to those with known risk factors for stroke and their families, who often make the decision to call an ambulance.

Postoperative seizure outcome in a series of 114 patients with supratentorial arteriovenous malformations

The incidence of de novo and ongoing postoperative seizures and factors implicated in an increased likelihood of seizures following supratentorial cerebral arteriovenous malformation (AVM) resection remain controversial. We investigated the frequency, severity and variables associated with postoperative seizures in 114 consecutive patients who underwent complete surgical excision of supratentorial AVMs at our institution. The minimal follow up period was 24 months. The incidence of seizures post-AVM surgery was 21% (less than half that found preoperatively). The incidence of postoperative seizures first manifesting >12 months post-AVM resection was 6.3%. A history of preoperative seizures was associated with an increased likelihood of multiple (> or =4) seizures >1 month post-AVM resection (chi2 = 4.38, P = 0.04). Poor functional neurological outcome at 12 months was also a risk factor for the development of > or =1 postoperative seizure using logistic regression analysis (P = 0.04, odds ratio 1.52, 95% CI 1.01-2.28). Cessation of AED therapy in all patients who remain seizure-free at 12 months post-AVM resection is appropriate due to a low risk of new seizure onset or seizure recurrence.

Stereoselective interaction of thiopentone enantiomers with the GABAA receptor

As pharmacokinetic differences between the thiopentone enantiomers seem insufficient to explain the ∼2 fold greater potency for CNS effects of (−)‐S‐ over (+)‐R‐thiopentone, this study was performed to determine any enantioselectivity of thiopentone at the GABAA receptor, the primary receptor for barbiturate hypnotic effects. Two electrode voltage clamp recording was performed on Xenopus laevis oocytes expressing human GABAA receptor subtype α1β2γ2 to determine relative differences in potentiation of the GABA response by rac‐, (+)‐R‐ and (−)‐S‐thiopentone, and rac‐pentobarbitone. Changes in the cellular environment pH and in GABA concentrations were also evaluated. With 3 μM GABA, the EC50 values were (−)‐S‐thiopentone (mean 26.0±s.e.mean 3.2 μM, n=9 cells) >rac‐thiopentone (35.9±4.2 μM, n=6, P=0.1) >(+)‐R‐thiopentone (52.5±5.0 μM, n=8, P<0.02) >rac‐pentobarbitone (97.0±11.2 μM, n=11, P<0.01). Adjustment of environment pH to 7.0 or 8.0 did not alter the EC50 values for (+)‐R‐ or (−)‐S‐thiopentone. Uninjected oocytes responded to >100 μM (−)‐S‐ and R‐thiopentone. This direct response was abolished by intracellular oocyte injection of 1,2‐bis(2‐aminophenoxy)ethane‐N,N,N1,N1‐tetraacetic acid (BAPTA), a Ca2+ chelating agent. With BAPTA, the EC50 values were (−)‐S‐thiopentone (20.6±3.2 μM, n=8) <(+)‐R‐thiopentone (36.2±3.2 μM, n=9, P<0.005). (−)‐S‐thiopentone was found to be ∼2 fold more potent than (+)‐R‐thiopentone in the potentiation of GABA at GABAA receptors expressed on Xenopus oocytes. This is consistent with the differences in potency for CNS depressant effects found in vivo.

Pharmacokinetics of Thiopental Enantiomers during and following Prolonged High-dose Therapy

BACKGROUND Thiopental is used as a racemate; however, this is not generally recognized. During conditions of prolonged high-dose therapy, the pharmacokinetics of thiopental may become nonlinear, but whether this derives from one or both enantiomers has not been evaluated. The authors determined the pharmacokinetics of R- and S-thiopental and serum concentrations of R- and S-pentobarbital from prolonged high-dose infusion of thiopental for neuroprotection. METHODS Twenty patients received a mean thiopental dose of 41.2 g over a mean duration of 95 h. R- and S-thiopental enantiomer serum concentration-time data from 18 patients were fitted with two models: a linear one-compartment model with first-order output, and a nonlinear one-compartment model with Michaelis-Menten output. RESULTS Nonlinear models were preferred in 16 of 18 patients. Paired analysis indicated that steady state clearance (Clss) and volume of distribution (Vd) were higher for R-thiopental (0.108 vs. 0.096 l/min, P < 0.0001; and 313 vs. 273 l, P < 0.0005, respectively); maximal rate of metabolism (Vm) was higher for S- than for R-thiopental (1.01 vs. 0.86 mg x l(-1) x h(-1), P = 0.02); elimination half-lives did not differ (14.6 vs. 14.7 h, P = 0.8); unbound fractions (f(u)) of R- and S-thiopental were 0.20 and 0.18, respectively, P < 0.0001). The differences in mean Clss, Vd and Vm were not significant when adjusted by f(u). Plasma concentrations of R- and S-pentobarbital were relatively small and unlikely to be of clinical significance. CONCLUSION The pharmacokinetics of R- and S-thiopental became nonlinear at these doses. The pharmacokinetic differences between R- and S-thiopental, although small, were statistically significant and were influenced by the higher f(u) of R-thiopental.

The neurologic manifestations of the acute porphyrias

The porphyrias are diseases characterised by accumulation of porphyrins and porphyrin precursors owing to enzymatic deficiencies of the haem synthetic pathway. In the acute hepatic porphyrias accumulation of porphyrin precursors, in particular delta-aminolaevulinic acid (ALA), cause dysfunction of the central, peripheral and autonomic nervous systems. This leads to the characteristic clinical findings of abdominal pain, neuropsychiatric symptoms and neuropathy. The exact pathogenic mechanism is not clear but evidence to date suggests both direct toxic effects of ALA and intracellular metabolic derangement contribute to the neurologic disorders. This review explores the mechanisms of neural dysfunction in the acute porphyrias and the resultant clinical features of an acute attack.

Alterations in cerebral potentials evoked by rectal distension in irritable bowel syndrome

OBJECTIVE:Central nervous system correlates of the visceral hyperalgesia documented in patients with irritable bowel syndrome are limited. Reproducible cerebral evoked potentials can be recorded in response to rhythmic balloon distension of the rectum in healthy adults. Irritable bowel syndrome patients and healthy subjects were studied to compare the characteristics of mechanically-evoked rectal cerebral potentials obtained during fasting and after the ingestion of a standard meal.METHODS:Twenty-two pairs of age-matched healthy female subjects and female irritable bowel syndrome patients were studied. Cerebral evoked potentials were recorded in response to rhythmic rectal distension (two distension series each of 100 repetitions at 0.8 hertz); cerebral evoked potential recordings were repeated after a 1000 kcal (46% fat) liquid meal. Trait and state anxiety questionnaires were also completed.RESULTS:Compared to healthy subjects, irritable bowel syndrome patients demonstrated higher prevalence of cerebral evoked potential early peaks (latency < 100 ms) postprandially, and uniformly shorter cerebral evoked potential latencies both before and after feeding.CONCLUSION:These findings provide further objective evidence for defective visceral afferent transmission in irritable bowel syndrome patients.

Parkinsonism–hyperpyrexia syndrome: The role of electroconvulsive therapy

Herein, we present a case of a parkinsonism-hyperpyrexia syndrome (PHS) in a 58-year-old man with a 10-year history of Parkinsons disease. The patient presented with a 2-week history of fever and increasing confusion, in the context of a number of changes to his medication regimen. On presentation, he was noted to be febrile with autonomic instability, diaphoresis and marked rigidity. He was disoriented and responding to visual hallucinations. Investigations revealed an elevated creatine kinase and a provisional diagnosis of PHS was made. After the patient failed to respond during a 2-week period to supportive measures, electroconvulsive therapy (ECT) treatment was commenced. A good response to eight bilateral ECT treatments was achieved, with resolution of his confusional state and associated psychotic phenomena. We discuss the nosological and management issues associated with this case and discuss the role of ECT as a treatment modality in this condition.

Brain histopathology in three cases of Susac's syndrome: implications for lesion pathogenesis and treatment

Susacs syndrome (SS) is the triad of encephalopathy, branch retinal artery occlusions and sensorineural hearing loss. While rare, it has become increasingly recognised since characteristic ‘snowball’ corpus callosum lesions were appreciated on MRI.1 We present clinical and histopathological findings on three patients with SS. Our findings demonstrate a T-cell-mediated inflammatory contribution to lesion pathogenesis. Treatment with the tumour necrosis factor (TNF) inhibitor, infliximab was beneficial in two patients, including in one previously reported,2 and in another who failed rituximab. This report provides a histological rationale for the observed benefit of infliximab, and suggests that infliximab should be considered as an adjunct therapy in patients with refractory SS. Three patients with SS most recently diagnosed among the authors’ practices who had undergone brain biopsy as part of their diagnostic clinical workup were identified. The clinical features, radiology, treatment and outcomes for the three patients are presented as online supplementary data (tables S1–S5 and figures S1 and S2). Extensive serum autoantibody screening was negative. Headache was present in all patients, highlighting the fact that it is a common manifestation of encephalopathy in SS. All three cases reported relatively non-specific auditory and visual symptoms, emphasising that fluorescein angiography±audiology testing should be considered in the diagnostic workup of patients with unexplained encephalopathy. Two patients underwent cerebellar biopsies and one a frontal lobe biopsy. One biopsy was from a treatment-naive patient (case 1). All contained variable numbers of wedge-shaped microinfarcts surrounded by microglia. In cerebellar biopsies (cases 1 and 3), …